Curcumin and Resveratrol as Dual Modulators of the STAT3 Pathway in Lung Cancer: A Comprehensive Review

Abstract

Lung cancer, primarily consisting of nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant health challenge despite advancements in treatment. This comprehensive review investigates the therapeutic potential of natural compounds curcumin (CUR) and resveratrol (RES) in targeting the STAT3 signaling pathway, which plays a crucial role in lung cancer progression and metastasis. Specifically, CUR inhibits STAT3 phosphorylation and activation in lung cancer cells, leading to a 40%-60% reduction in tumor size and a significant decrease in the expression of STAT3 target genes such as cyclin D1, VEGF, MMP2, and MMP9. RES demonstrates similar effects by suppressing STAT3 signaling, resulting in a 30%-50% reduction in tumor growth and a marked decrease in the M2 polarization of tumor-associated macrophages, thereby disrupting the communication between cancer cells and the tumor microenvironment. CUR analogues, such as L48H37 and compound 5 k, also exhibit anticancer effects by blocking the STAT3 pathway. L48H37 suppresses the motility, migration, and invasion of human osteosarcoma cells by inhibiting the JAK/STAT pathway and urokinase plasminogen activator (uPA) expression. Compound 5 k inhibits NSCLC cell growth by regulating the NF-κB/STAT3 signaling pathways. RES inhibits STAT3 activation and downstream signaling in NSCLC cells, reducing cell migration and invasion while increasing apoptosis by 20%-30%. In vivo studies show that RES can suppress tumor growth by 40%-50% by inhibiting the STAT3/HIF-1α/VEGF axis. RES also shows promise in overcoming drug resistance in SCLC by inhibiting the STAT3/VEGF pathway and P-glycoprotein function, potentially resensitizing resistant cells to chemotherapy. These findings underscore the potential of CUR and RES as promising therapeutic agents against lung cancer by targeting the STAT3 signaling pathway and related processes such as angiogenesis, metastasis, and drug resistance. Further research is needed to optimize their bioavailability, understand their molecular mechanisms, and assess their clinical efficacy in combination with standard therapies.

Keywords: JAK2/STAT3 signaling pathway; STAT3; curcumin; lung cancer; resveratrol.

FIGURE 1

STAT3 signaling is initiated when various ligands bind to their receptors on the cell surface, resulting in the phosphorylation of STAT3. Additionally, nonreceptor tyrosine kinases Src and Abl also directly phosphorylate STAT3. The phosphorylated STAT3 then forms homodimers and translocates to the nucleus. Once in the nucleus, STAT3 regulates gene expression in cellular proliferation and survival, such as CyclinD1, c‐Myc, Survivin, Bcl‐XL, and Mcl1. Moreover, STAT3 upregulates the expression of VEGF, bFGF, HGF, and HIF1α, which participate in processes related to cancer progression. Furthermore, STAT3 promotes invasion and migration by regulating MMP2, MMP9, Twist, and Vimentin expression. It also downregulates immune surveillance by promoting the secretion of chemokines like CXCL10. In addition, STAT3 plays a role in maintaining cancer stem cell properties by regulating the expression of Oct3/4, Nanog, CD133, and CD44.

FIGURE 2

Effects of CUR in treating lung cancer by targeting the STAT3 signaling pathway. This figure shows how CUR acts as a therapeutic agent for lung cancer treatment by inhibiting multiple pathways. Through inhibition, CUR downregulates JAK2/STAT3 signaling pathway activity, leading to reduced phosphorylation of JAK2 and STAT3 proteins in both a time and dose‐dependent manner. Additionally, CUR inhibits IL‐6 inducible STAT3 phosphorylation, which targets the IL‐6/JAK/STAT3 pathway specifically in SCLC treatment. Furthermore, CUR inhibits STAT3 phosphorylation, resulting in downregulation of several STAT3 downstream targets including Cyclin D1, Cyclin B1, and Mcm2.

FIGURE 3

Effects of RES in treating lung cancer by targeting the STAT3 signaling pathway. This figure illustrates how RES acts as a therapeutic agent for lung cancer treatment through multiple pathways. RES inhibits the expression of STAT3, HIF‐1α, and VEGF, leading to reduced lung cancer growth and metastasis. Through suppression of the STAT3/HIF‐1α/VEGF pathway, it provides a potential avenue for treating NSCLC. Additionally, RES possesses antimetastatic properties by exerting inhibitory effects on P‐glycoprotein activity and targeting tumor‐associated macrophages. The compound's ability to suppress the inflammatory microenvironment and modulate multiple signaling pathways makes it a promising therapeutic agent for lung cancer treatment.